Regarding a herbicidal compound having the chemical structure of thiopheneisoxazoline, U.S. Pat. No. 6,838,416 B2 discloses a thiopheneisoxazoline compound represented by Formula 4 below.

(wherein, X1, X2, and X3 represent each a hydrogen atom, an alkyl group, a halogen group, a methoxy group, or a nitro group, and Y1, Y2, and Y3 represent each a hydrogen atom or a fluorine atom).
This patent document discloses that in the synthetic procedure of thiopheneisoxazoline derivatives including the compound of Formula 1, coupling reaction is performed using sodium hydride as a base in an anhydrous condition. However, this method is appropriate only for small-scale synthesis in a laboratory, and is not appropriate for industrial large-scale production.
A prior art [J. Agric. Food Chem. 2005, 53, 8639-8643] describes the method for the preparation of methiozolin based on this patent in detail. The prior art discloses that according to Reaction Scheme 1, 4,5-dihydro-5-methyl-3-{(3-methylthiophene-2-yl)-isoxazole-5-yl}methanol (Formula 2) and 2,6-difluorobenzylbromide (Formula 3) are reacted employing sodium hydride as a base in a DMF solvent at a temperature of 60 to 70° C., and after completion of the reaction the reaction mixture is diluted with an organic solvent, washed with water and the resulting organic layer is concentrated, and then subjected to column chromatography to perform pre-purification, and then, the obtained pre-purified product is crystallized in n-hexane to obtain a target material in the yield of about 60%. However, this method is applicable only to small-scale laboratorial synthesis because an anhydrous condition is required to use sodium hydride as a base, and after reaction, column chromatography must be performed as a pre-purification procedure to remove mineral oil contained in sodium hydride, and is not appropriate for industrial synthesis for mass production.
Another prior art [Bull. Korean Chem. Soc. 2012, Vol. 33, No. 1, 297-300] describes a method of producing (R)-methiozolin (Formula 1a) or (S)-methiozolin (Formula 1 b) that is a methiozolin stereoisomer, in which according to Reaction Scheme 2 and Reaction Scheme 3, (R) or (S) 4,5-dihydro-5-methyl-3-{(3-methylthiophene-2-yl)-isoxazole-5-yl}methanol (Formula 2a or Formula 2b) and 2,6-difluorobenzylchloride (Formula 3) are reacted employing sodium hydroxide as a base in THF solvent at a temperature of 60-70° C., and after completion of the reaction the reaction mixture is diluted with an organic solvent, washed with water and the resulting organic layer is concentrated, and then subjected to column chromatography to perform pre-purification, and the pre-purified product is crystallized in n-hexane to obtain a target material in the yield of about 60%. In this case, the yield is also low, and due to the pre-purification procedure employing column chromatography, this method is not appropriate for industrial synthesis for mass production.

U.S. Pat. No. 6,838,416 B2 discloses that methiozolin of Formula 1 is suitable for a paddy rice herbicide, and U.S. Pat. No. 7,998,902 discloses that methiozolin is suitable for a turf herbicide. However, when impurities other than methiozolin are included in the manufacturing process for commercialization of methiozolin, the impurities included may cause toxicity or environmental problems. Accordingly, when produced in great quantities, methiozolin, which is a target material, needs to be produced in as high purity as possible.
As described above, to commercialize methiozolin of Formula 1 as herbicide, there is a need to develop an industrial process that is applicable for mass production of high-purity methiozoline in high yield.